UNASSIGNED: Genomic variations in mono-ADP ribosylhydrolase 2 (MACROD2) have been associated with autism spectrum disorder (ASD) in recent genome-wide studies and case reports. In this study, we aimed to evaluate the MACROD2 expression profile in patients with ASD.
UNASSIGNED: The study group included 100 children with a DSM-5 diagnosis of ASD, and the control group consisted of 105 healthy controls. Blood samples were obtained from all participants in this study, and the gene expression level was determined using quantitative reverse transcription PCR (RT-qPCR). Statistical analysis was performed with R 3.4.0 and Statistical Program for Social Sciences (SPSS for Windows, 21.0).
UNASSIGNED: The mean ages of the participants in the study and control groups were 9.22 ± 3.62 and 9.27 ± 3.86 years, respectively. There was no significant difference concerning gender (P = .944) and age (P = .914) between the 2 groups. MACROD2 gene expression was found to be decreased in the study group compared to the control group (study group = 5.73, control group = 89.56; fold change =-3.967; P < .001). While the level of MACROD2 expression was not correlated with the ASD severity, it was associated with the severity of the hyperactivity/impulsivity symptoms (P = .008).
UNASSIGNED: This is the first study in the literature investigating the peripheral expression of the MACROD2 gene. We showed that the expression level of MACROD2 was decreased in patients with ASD when compared to the control group. As the relationship between the MACROD2 gene expression profile and ASD remains to be further investigated, this study may provide an insight for further studies.

Changes in gut microbiota composition and in epigenetic mechanisms have been proposed to play important roles in energy homeostasis, and the onset and development of obesity. However, the crosstalk between epigenetic markers and the gut microbiome in obesity remains unclear. The main objective of this study was to establish a link between the gut microbiota and DNA methylation patterns in subjects with obesity by identifying differentially methylated DNA regions (DMRs) that could be potentially regulated by the gut microbiota. DNA methylation and bacterial DNA sequencing analysis were performed on 342 subjects with a BMI between 18 and 40 kg/m2. DNA methylation analyses identified a total of 2648 DMRs associated with BMI, while ten bacterial genera were associated with BMI. Interestingly, only the abundance of Ruminococcus was associated with one BMI-related DMR, which is located between the MACROD2/SEL1L2 genes. The Ruminococcus abundance negatively correlated with BMI, while the hypermethylated DMR was associated with reduced MACROD2 protein levels in serum. Additionally, the mediation test showed that 19% of the effect of Ruminococcus abundance on BMI is mediated by the methylation of the MACROD2/SEL1L2 DMR. These findings support the hypothesis that a crosstalk between gut microbiota and epigenetic markers may be contributing to obesity development.

High-risk HPV is clearly associated with cervical cancer. Integration of HPV DNA into the host genome is considered a key event in driving cervical carcinogenesis. However, the mechanism on how HR-HPV integration influences the host genome structure has remained enigmatic.
In our study, 25 DNA samples including 11 from fresh-frozen cervical carcinomas and 14 from fresh-frozen high-grade squamous intraepithelial lesion (HSILs) were detected using the method of HPV capture combined with next generation sequencing.
We calculated the frequency in each viral gene or region and found that breakpoints were prone to occur in L1 and L2 instead of E2 in the cervical cancer (P = 0.0004 and P = 5.15 × 10-40) and HSIL group (P = 2.1 × 10-32 and P = 7.06 × 10-13). The results revealed that HPV16 showed a strong tendency toward intronic region (P = 5.02 × 10-64) but a subtle tendency toward intergenic region (P = 0.04). The most frequent integration site was in the MACROD2 gene (introns 2, 4, 5, 6, 8 and 9), which in MACROD2 functional domain.
Our results revealed that MACROD2 is HPV hot spot integration site in cervical lesions, and its deficiency alter DNA repair and sensitivity to DNA damage thought impaired PARP1 activity resulting in chromosome instability.

Adenosine diphosphate ribosylation (ADP-ribosylation; ADPr), the addition of ADP-ribose moieties onto proteins and nucleic acids, is a highly conserved modification involved in a wide range of cellular functions, from viral defence, DNA damage response (DDR), metabolism, carcinogenesis and neurobiology. Here we study MACROD1 and MACROD2 (mono-ADP-ribosylhydrolases 1 and 2), two of the least well-understood ADPr-mono-hydrolases. MACROD1 has been reported to be largely localized to the mitochondria, while the MACROD2 genomic locus has been associated with various neurological conditions such as autism, attention deficit hyperactivity disorder (ADHD) and schizophrenia; yet the potential significance of disrupting these proteins in the context of mammalian behaviour is unknown. Therefore, here we analysed both Macrod1 and Macrod2 gene knockout (KO) mouse models in a battery of well-defined, spontaneous behavioural testing paradigms. Loss of Macrod1 resulted in a female-specific motor-coordination defect, whereas Macrod2 disruption was associated with hyperactivity that became more pronounced with age, in combination with a bradykinesia-like gait. These data reveal new insights into the importance of ADPr-mono-hydrolases in aspects of behaviour associated with both mitochondrial and neuropsychiatric disorders.

Post-translational modifications (PTM) of proteins are crucial for fine-tuning a cell\'s response to both intracellular and extracellular cues. ADP-ribosylation is a PTM, which occurs in two flavours: modification of a target with multiple ADP-ribose moieties (poly(ADP-ribosyl)ation or PARylation) or with only one unit (MARylation), which are added by the different enzymes of the PARP family (also known as the ARTD family). PARylation has been relatively well-studied, particularly in the DNA damage response. This has resulted in the development of PARP inhibitors such as olaparib, which are increasingly employed in cancer chemotherapeutic approaches. Despite the fact that the majority of PARP enzymes catalyse MARylation, MARylation is not as well understood as PARylation. MARylation is a dynamic process: the enzymes reversing intracellular MARylation of acidic amino acids (MACROD1, MACROD2, and TARG1) were discovered in 2013. Since then, however, little information has been published about their physiological function. MACROD1, MACROD2, and TARG1 have a \'macrodomain\' harbouring the catalytic site, but no other domains have been identified. Despite the lack of information regarding their cellular roles, there are a number of studies linking them to cancer. However, some of these publications oppose each other, some rely on poorly-characterised antibodies, or on aberrant localisation of overexpressed rather than native protein. In this review, we critically assess the available literature on a role for the hydrolases in cancer and find that, currently, there is limited evidence for a role for MACROD1, MACROD2, or TARG1 in tumorigenesis.

Copy number variation (CNV) is a common structural variation pattern of DNA, and it features a higher mutation rate than single-nucleotide polymorphisms (SNPs) and affects a larger fragment of genomes. CNV is related with the genesis of complex diseases and can thus be used as a strategy to identify novel cancer-predisposing markers or mechanisms. In particular, the frequent deletions of mono-ADP-ribosylhydrolase 2 (MACROD2) locus in human colorectal cancer (CRC) alters DNA repair and the sensitivity to DNA damage and results in chromosomal instability. The relationship between CNV and cancer has not been explained. In this study, on the basis of the genome variation profiling by the SNP array from 651 CRC primary tumors, we computationally analyzed the CNV data to select crucial SNP sites with the most relevance to three different states of MACROD2 (heterozygous deletion, homozygous deletion, and normal state), suggesting that these CNVs may play functional roles in CRC tumorigenesis. Our study can shed new insights into the genesis of cancer based on CNV, providing reference for clinical diagnosis, and treatment prognosis of CRC.

Split hand/foot malformation (SHFM) or ectrodactyly is a rare congenital disorder affecting limb development characterized by clinical and genetic heterogeneity. SHFM is usually inherited as an autosomal dominant trait with incomplete penetrance. Isolated and syndromic forms are described. The extent of associated malformations is highly variable and multiple syndromes with clinical and genetic overlap have been described. We report here a 28 year-old man presenting with SHFM, sparse hair and widespread freckles. Array-CGH identified a 450 kb de novo 20p12.1 microdeletion encompassing three exons (exon 6 to 8) of MACROD2. Although MACROD2 mutations have not been associated with limb malformation until now, it is located next to KIF16B, which is involved in fibroblast growth factor receptor (FGFR) signaling. Additionally, the deletion encompassed a histone modification H3K27ac mark, known as a provider of quantitative readout of promoter and enhancer activity during human limb development. Altogether, these findings suggest that the 20p12.1 CNV is causative of SHFM in the present case through disturbance of regulatory elements functioning.

Diagnosing a complex genetic syndrome and correctly assigning the concomitant phenotypic traits to a well-defined clinical form is often a medical challenge. In this work, we report the analysis of a family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly in the proband, with the aim of adding new aspects for obtaining a clear diagnosis. We performed array-comparative genomic hybridization and quantitative reverse transcriptase PCR (qRT-PCR) analyses. We identified a deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) in several members of the family. This gene is actually not associated with a specific syndrome but with congenital anomalies of multiple organs. qRT-PCR showed higher levels of a MACROD2 mRNA isoform in the individuals carrying the deletion. Our results, together with other data reported in the literature, support the hypothesis that the deletion in MACROD2 can affect correct embryonic development and that the presence of another associated event, such as epigenetic modifications at the MACROD2 locus, can influence the level of severity of the pathology.

ADP-ribosylation is an important post-translational protein modification that regulates diverse biological processes, controlled by dedicated transferases, and hydrolases. Disruption in the gene encoding for MACROD2, a mono-ADP-ribosylhydrolase, has been associated to the Kabuki syndrome, a pediatric congenital disorder characterized by facial anomalies, and mental retardation. Non-coding and structural mutations/variations in MACROD2 have been associated to psychiatric disorders, to obesity, and to cancer. Mechanistically, it has been recently shown that frequent deletions of the MACROD2 alter DNA repair and sensitivity to DNA damage, resulting in chromosome instability, and colorectal tumorigenesis. Whether MACROD2 deletion sensitizes the organism to metabolic and tumorigenic stressors, in absence of other genetic drivers, is unclear. As MACROD2 is ubiquitously expressed in mice, here we generated constitutively whole-body knock-out mice for MACROD2, starting from mouse embryonic stem (ES) cells deleted for the gene using the VelociGene® technology, belonging to the Knockout Mouse Project (KOMP) repository, a NIH initiative. MACROD2 knock-out mice were viable and healthy, indistinguishable from wild type littermates. High-fat diet administration induced obesity, and glucose/insulin intolerance in mice independent of MACROD2 gene deletion. Moreover, sub-lethal irradiation did not indicate a survival or lethality bias in MACROD2 knock-out mice compared to wild type littermates. Altogether, our data point against a sufficient role of MACROD2 deletion in aggravating high-fat induced obesity and DNA damage-associated lethality, in absence of other genetic drivers.

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